Fluorinated quinoline indoles as inhibitors of the biosynthesis of leukotrienes

ABSTRACT

This invention relates to compounds having the formula I: ##STR1## wherein R 1  is H, F or MeO, which are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea, and migraine.

CROSS REFERENCE

The compounds of Formula I' are described in U.S. Ser. No. 650,825 filedFeb. 5, 1991, which is now U.S. Pat. No. 5,204,344, and incorporatedherein by reference.

BACKGROUND OF THE INVENTION

European Patent Applications 166,591 and 275,667 disclose a series ofindole-based compounds with activity as prostaglandin antagonists andinhibitors of leukotriene biosynthesis respectively. In EP 181,568 andEP 200,101 are disclosed a series of compounds, containing two aromaticnuclei, which are described as possessing activity as lipoxygenaseinhibitors. In EP 279,263 is disclosed a series of indoles, benzofuransand benzothiophenes which are described as possessing activity aslipoxygenase inhibitors. U.S. Pat. No. 4,629,733 describes novelindolinones which are antithrombotic and inhibit both phosphodiesteraseand tumor metastasis. The chemical preparation of quinolylindoles isreferred to by Sheinkman, et al., Chem. Ab., Vol. 67, 54017 (1967),without mentioning any utility for such compounds. A number of N-acylderivatives of indole-3-acetic acid are described as potentialanti-inflammatory agents by Biniecki, et al., Chem. Ab., Vol. 98, 197936(1983), by Pakula, et al., Chem. Ab., Vol. 105, 190835 (1986), and inBritish Pat. Spec. 1,228,848.

EP 419,049 (Mar. 27, 1991) teaches (quinolin-2-ylmethoxy)indoles asinhibitors of leukotriene biosynthesis. WO 92/03132 (Mar. 5, 1992)teaches indole derivatives as inhibitors of leukotriene biosynthesis.

SUMMARY OF THE INVENTION

The present invention relates to fluorinated quinoline indoles havingactivity as leukotriene biosynthesis inhibitors, to methods for theirpreparation, and to methods and pharmaceutical formulations for usingthese compounds in mammals (especially humans).

Because of their activity as leukotriene biosynthesis inhibitors, thecompounds of the present invention are useful as anti-asthmatic,anti-allergic, and anti-inflammatory agents and are useful in treatingallergic rhinitis and chronic bronchitis and for amelioration of skindiseases like psoriasis and atopic eczema. These compounds are alsouseful to inhibit the pathologic actions of leukotrienes on thecardiovascular and vascular systems for example, actions such as resultin angina or endotoxin shock. The compounds of the present invention areuseful in the treatment of inflammatory and allergic diseases of theeye, including allergic conjunctivitis. The compounds are also useful ascytoprotective agents and for the treatment of migraine headache.

Thus, the compounds of the present invention may also be used to treator prevent mammalian (especially, human) disease states such as erosivegastritis; erosive esophagitis; inflammatory bowel disease;ethanol-induced hemorrhagic erosions; hepatic ischemia; noxiousagent-induced damage or necrosis of hepatic, pancreatic, renal, ormyocardial tissue; liver parenchymal damage caused by hepatoxic agentssuch as CCl₄ and D-galactosamine; ischemic renal failure;disease-induced hepatic damage; bile salt induced pancreatic or gastricdamage; trauma- or stress-induced cell damage; and glycerol-inducedrenal failure.

The compounds of this invention are inhibitors of the biosynthesis of5-lipoxygenase metabolites of arachidonic acid, such as 5-HPETE, 5-HETEand the leukotrienes. Leukotrienes B₄, C₄, D₄ and E₄ are known tocontribute to various disease conditions such as asthma, psoriasis,pain, ulcers and systemic anaphylaxis. Thus inhibition of the synthesisof such compounds will alleviate these and other leukotriene-relateddisease states.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are within the scope of Formula I':##STR2## wherein: R¹, R², R³, R⁴ and R¹⁰ are independently hydrogen,halogen, lower alkyl, lower alkenyl, lower alkynyl, --CF₃, --CN, --NO₂,--N₃, --C(OH)R¹¹ R¹¹, --CO₂ R¹², --SR¹⁴, --S(O)R¹⁴, --S(O)₂ R¹⁴, --S(O)₂NR¹⁵ R¹⁵, --OR¹⁵, --NR¹⁵ R¹⁵, --C(O)R¹⁶ or --(CH₂)_(t) R²¹ ;

R⁵ is hydrogen, --CH₃, CF₃, --C(O)H, X¹ --R⁶ or X² --R⁷ ;

R⁶ and R⁹ are independently alkyl, alkenyl, --(CH₂)_(u) Ph(R¹⁰)₂ or--(CH₂)_(u) Th(R¹⁰)₂ ;

R⁷ is --CF₃ or R⁶ ;

R⁸ is hydrogen or X³ --R⁹ ;

each R¹¹ is independently hydrogen or lower alkyl, or two R¹¹ 's on samecarbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;

R¹² is hydrogen, lower alkyl or --CH₂ R²¹ ;

R¹³ is lower alkyl or --(CH₂)_(r) R²¹ ;

R¹⁴ is --CF₃ or R¹³ ;

R¹⁵ is hydrogen, --C(O)R¹⁶, R¹³, or two R¹⁵ 's on the same nitrogen maybe joined to form a monocyclic heterocyclic ring of 4 to 6 atomscontaining up to 2 heteroatoms chosen from O, S or N;

R¹⁶ is hydrogen, --CF₃, lower alkyl, lower alkenyl, lower alkynyl or--(CH₂)_(r) R₂₁ ;

R¹⁷ is --(CH₂)_(s) --C(R¹⁸ R¹⁸)--(CH₂)_(s) --R¹⁹ or --CH₂ C(O)NR¹⁵ R¹⁵ ;

R¹⁸ is hydrogen or lower alkyl;

R¹⁹ is a) a monocyclic or bicyclic heterocyclic ring containing from 3to 9 nuclear carbon atoms and 1 or 2 nuclear hetero-atoms selected fromN, S or O and with each ring in the heterocyclic radical being formed of5 or 6 atoms, or b) the radical W--R²⁰ ;

R²⁰ is alkyl or --C(O)R²³ ;

R²¹ is phenyl substituted with 1 or 2 R²² groups;

R²² is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio,lower alkylsulfonyl, lower alkylcarbonyl, --CF₃, --CN, --NO₂ or --N₃ ;

R²³ is alkyl, cycloalkyl, or monocyclic monoheterocyclic ring;

R²⁴ is the residual structure of a standard amino acid, or R¹⁸ and R²⁴attached to the same N can cyclize to form a proline residue;

m is 0 to 1;

n is 0 to 3;

p is 1 to 3 when m is 1;

p is 0 to 3 when m is 0;

r is 0 to 2;

s is 0 to 3;

t is 0 to 2;

u is 0 to 3;

v is 0 or 1;

W is 0, S or NR¹⁵ ;

X¹ is 0, or NR¹⁵ ;

X² is C(O), CR¹¹ R¹¹, S, S(O) or S(O)₂ ;

X³ is C(O), CR¹¹ R¹¹, S(O)₂ or a bond;

X⁴ is CH═CH, CH₂ --Y¹ or Y¹ --CH₂ ;

Y is X¹ or X² ;

Y¹ is O, S, S(O)₂ or CH₂ ;

Q is --CO₂ R¹², --C(O)NHS(O)₂ R¹⁴, --NHS(O)₂ R¹⁴,

--S(O)₂ NHR¹⁵ --C(O)NR¹⁵ R¹⁵, --CO₂ R¹⁷, --C(O)NR¹⁸ R²⁴, --CH₂ OH, or1H-- or 2H-tetrazol-5-yl;

or the pharmaceutically acceptable salts thereof.

Specifically, the present invention provides compounds of the formula I:##STR3## wherein R¹ is H, F or MeO, or the pharmaceutically acceptablesalts thereof.

Definitions

The following abbreviations have the indicated meanings:

Me=methyl

Bz=benzyl

Ph=phenyl

t-Bu=tert-butyl

i-Pr=isopropyl

c-C₆ H₁₁ =cyclohexyl

c-Pr=cyclopropyl

c-=cyclo

Ac=acetyl

Tz=1H- or 2H-tetrazol-5-yl

Th=2- or 3-thienyl

c-C₅ H₉ =cyclopentyl

1-Ad=1-adamantyl.

Alkyl, alkenyl, and alkynyl are intended to include linear, branched,and cyclic structures and combinations thereof.

As used herein, the term "alkyl" includes "lower alkyl" and extends tocover carbon fragments having up to 20 carbon atoms. Examples of alkylgroups include octyl, nonyl, norbornyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl,cyclododecyl, adamantyl, and the like.

As used herein, the term "lower alkyl" includes those alkyl groups offrom 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,2-methylcyclopropyl, cyclopropylmethyl, and the like.

The term "cycloalkyl" refers to a hydrocarbon ring having from 3 to 7carbon atoms. Examples of cycloalkyl groups are cyclopropyl,cyclopentyl, cycloheptyl and the like.

"Lower alkenyl" groups include those alkenyl groups of 2 to 7 carbonatoms. Examples of lower alkenyl groups include vinyl, allyl,isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyland the like.

"Lower alkynyl" groups include those alkynyl groups of 2 to 7 carbonatoms. Examples of lower alkynyl groups include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

As used herein, the term "lower alkoxy" includes those alkoxy groups offrom 1 to 7 carbon atoms of a straight, branched, or cyclicconfiguration. Examples of lower alkoxy groups include methoxy, ethoxy,propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.

As used herein the term "lower alkylthio" includes those alkylthiogroups of from 1 to 7 carbon atoms of a straight, branched or cyclicconfiguration. Examples of lower alkylthio groups include methylthio,propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration,the propylthio group signifies --SCH₂ CH₂ CH₃.

The term "monocyclic monoheterocyclic ring" which defines R²³ includesthose monocyclic groups of 5 to 7 members containing only 1 heteroatomselected from N, S or O in the ring. Examples include tetrahydrofuran,tetrahydrothiophene, pyrrolidine, piperidine, tetrahydropyran, and thelike.

The term "monocyclic or bicyclic heterocyclic ring" which defines R¹⁹may be 2,5-dioxo-1-pyrrolidinyl, (3-pyridinylcarbonyl) amino,1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-dihydro-2H-isoindol-2-yl,2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl, 2-imidazolyl,2-oxo-1,3-dioxolen-4-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yland the like.

The point of attachment of any heterocyclic ring may be at any freevalence of the ring.

It is understood in the art that when the variable v is 1, the nitrogenof the quinolinyl N-oxide so formed is positively charged, and theoxygen is negatively charged.

The term standard amino acid is employed to include the following aminoacids: alanine, asparagine, aspartic acid, arginine, cysteine, glutamicacid, glutamine, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine and valine. (See F. H. C. Crick, Symposium of the Society forExperimental Biology, 1958 (12) p. 140.)

It is understood that R¹ and R² may be located at any of positions3,4,5,6,7 or 8 of the quinoline ring.

The terms Ph(R¹⁰)₂ and Th(R¹⁰)₂ indicate a phenyl or thienyl groupsubstituted with two R¹⁰ substituents.

Halogen includes F, Cl, Br, and I.

It is intended that the definitions of any substituent (e.g., R¹, R²,R¹⁵, Ph(R¹⁰)₂, etc.) in a particular molecule be independent of itsdefinitions elsewhere in the molecule. Thus, --NR¹⁵ R¹⁵ represents--NHH, --NHCH₃, --NHC₆ H₅, etc.

The monocyclic heterocyclic rings formed when two R¹⁵ groups jointhrough N include pyrrolidine, piperidine, morpholine, thiamorpholine,piperazine, and N-methylpiperazine.

The prodrug esters of Q (i.e., when Q=CO₂ R¹⁷) are intended to includethe esters such as are described by Saari et al., J. Med. Chem., 21, No.8, 746-753 (1978), Sakamoto et al., Chem. Pharm. Bull., 32, No. 6,2241-2248 (1984) and Bundgaard et al., J. Med. Chem., 30, No. 3, 451-454(1987).

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt, thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc and the like. Particularlypreferred are the ammonium, calcium, magnesium, potassium and sodiumsalts. Salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N¹ -dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and thelike. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids.

It will be understood that in the discussion of methods of treatmentwhich follows, references to the compounds of Formula I are meant toalso include the pharmaceutically acceptable salts.

The ability of the compounds of Formula I to inhibit biosynthesis of theleukotrienes makes them useful for inhibiting the symptoms induced bythe leukotrienes in a human subject. This inhibition of the mammalianbiosynthesis of leukotrienes indicates that the compounds andpharmaceutical compositions thereof are useful to treat, prevent orameliorate in mammals and especially in humans: 1) pulmonary conditionsincluding diseases such as asthma, 2) allergies and allergic reactionssuch as allergic rhinitis, contact dermatitis, allergic conjunctivitis,and the like, 3) inflammation such as arthritis or inflammatory boweldisease, 4) pain, 5) skin conditions such as psoriasis and the like, 6)cardiovascular conditions such as angina, endotoxin shock, and the likeand 7) renal insufficiency arising from ischaemia induced byimmunological or chemical (cyclosporin) etiology, and that the compoundsare cytoprotective agents.

The cytoprotective activity of a compound may be observed in bothanimals and man by noting the increased resistance of thegastrointestinal mucosa to the noxious effects of strong irritants, forexample, the ulcerogenic effects of aspirin or indomethacin. In additionto lessening the effect of non-steroidal anti-inflammatory drugs on thegastrointestinal tract, animal studies show that cytoprotectivecompounds will prevent gastric lesions induced by oral administration ofstrong acids, strong bases, ethanol, hypertonic saline solutions and thelike.

Two assays can be used to measure cytoprotective ability. These assaysare; (A) an ethanol-induced lesion assay and (B) an indomethacin-inducedulcer assay and are described in EP 140,684.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range for anti-asthmatic, anti-allergic or anti-inflammatory useand generally, uses other than cytoprotection, lie within the range offrom about 0.001 mg to about 100 mg per kg body weight of a mammal,preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1mg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range for anti-asthmatic, anti-inflammatory oranti-allergic use is from about 0.001 mg to about 25 mg (preferably from0.01 mg to about 1 mg) of a compound of Formula I per kg of body weightper day and for cytoprotective use from about 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 1 mg to about 10 mg) of a compound of Formula I per kg of bodyweight per day.

In the case where an oral composition is employed, a suitable dosagerange for anti-asthmatic, anti-inflammatory or anti-allergic use is,e.g. from about 0.01 mg to about 100 mg of a compound of Formula I perkg of body weight per day, preferably from about 0.1 mg to about 10 mgper kg and for cytoprotective use from 0.1 mg to about 100 mg(preferably from about 1 mg to about 100 mg and more preferably fromabout 10 mg to about 100 mg) of a compound of Formula I per kg of bodyweight per day.

For the treatment of diseases of the eye, ophthalmic preparations forocular administration comprising 0.001-1% by weight solutions orsuspensions of the compounds of Formula I in an acceptable ophthalmicformulation may be used.

The exact amount of a compound of the Formula I to be used as acytoprotective agent will depend on, inter alia, whether it is beingadministered to heal damaged cells or to avoid future damage, on thenature of the damaged cells (e.g., gastrointestinal ulcerations vs.nephrotic necrosis), and on the nature of the causative agent. Anexample of the use of a compound of the Formula I in avoiding futuredamage would be co-administration of a compound of the Formula I with anon-steroidal anti-inflammatory drug (NSAID) that might otherwise causesuch damage (for example, indomethacin). For such use, the compound ofFormula I is administered from 30 minutes prior up to 30 minutes afteradministration of the NSAID. Preferably it is administered prior to orsimultaneously with the NSAID, (for example, in a combination dosageform).

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. Theterm "pharmaceutically acceptable salts" refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids including inorganicbases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulisers. The compounds may also bedelivered as powders which may be formulated and the powder compositionmay be inhaled with the aid of an insufflation powder inhaler device.The preferred delivery system for inhalation is a metered doseinhalation (MDI) aerosol, which may be formulated as a suspension orsolution of Compound I in suitable propellants, such as fluorocarbons orhydrocarbons.

Suitable topical formulations of Compound I include transdermal devices,aerosols, creams, ointments, lotions, dusting powders, and the like.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 2.5 mg toabout 500 mg of the active ingredient and each cachet or capsulecontains from about 2.5 to about 500 mg of the active ingredient.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

    ______________________________________                                        Injectable Suspension (I.M.)                                                                         mg/ml                                                  ______________________________________                                        Compound of Formula I  10                                                     Methylcellulose        5.0                                                    Tween 80               0.5                                                    Benzyl alcohol         9.0                                                    Benzalonium chloride   1.0                                                    Water for injection                                                           to a total volume of 1 ml                                                     ______________________________________                                        Tablet                 mg/tablet                                              ______________________________________                                        Compound of Formula I  25                                                     Microcrystalline Cellulose                                                                           415                                                    Providone              14.0                                                   Pregelatinized Starch  43.5                                                   Magnesium Stearate     2.5                                                                           500                                                    ______________________________________                                        Capsule                mg/capsule                                             ______________________________________                                        Compound of Formula I  25                                                     Lactose Powder         573.5                                                  Magnesium Stearate     1.5                                                                           600                                                    ______________________________________                                        Aerosol                Per canister                                           ______________________________________                                        Compound of Formula I  24 mg                                                  Lecithin, NF Liquid Concentrate                                                                      1.2 mg                                                 Trichlorofluoromethane, NF                                                                           4.025 gm                                               Dichlorodifluoromethane, NF                                                                          12.15 gm                                               ______________________________________                                    

In addition to the compounds of Formula I, the pharmaceuticalcompositions of the present invention can also contain other activeingredients, such as cyclooxygenase inhibitors, non-steroidalanti-inflammatory drugs (NSAIDs), peripheral analgesic agents such aszomepirac diflunisal and the like. The weight ratio of the compound ofthe Formula I to the second active ingredient may be varied and willdepend upon the effective dose of each ingredient. Generally, aneffective dose of each will be used. Thus, for example, when a compoundof the Formula I is combined with an NSAID the weight ratio of thecompound of the Formula I to the NSAID will generally range from about1000:1 to about 1:1000, preferably about 200:1 to about 1:200.Combinations of a compound of the Formula I and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: alminoprofen,benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen,flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen,oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, andtioxaprofen. Structurally related propionic acid derivatives havingsimilar analgesic and anti-inflammatory properties are also intended tobe included in this group.

Thus, "propionic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻Na⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac. Structually related acetic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs having a free --CH₂COOH group (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: flufenamicacid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamicacid. Structurally related fenamic acid derivatives having similaranalgesic and anti-inflammatory properties are also intended to beencompassed by this group.

Thus, "fenamic acid derivatives" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs which contain the basicstructure: ##STR4## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and anti-inflammatory propertiesare also intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenon-narcotic analgesics/non-steroidal anti-inflammatory drugs whichcontain the basic structure: ##STR5## which can bear a variety ofsubstituents and in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO⁻ Na⁺.

The oxicams which can be used in the present invention comprise:isoxicam, piroxicam, sudoxicam and tenoxican. Structurally relatedoxicams having similar analgesic and anti-inflammatory properties arealso intended to be encompassed by this group.

Thus, "oxicams" as defined herein are non-narcoticanalgesics/non-steroidal anti-inflammatory drugs which have the generalformula: ##STR6## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: amfenac sodium, aminoprofen,anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine,beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate,dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein,di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam,epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate,fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin,flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen,glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen,isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium,lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium,meseclazone, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin,oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen,sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone,thielavin B, tiaramide HCl, tiflamizole, timegadine, tolpadol, tryptamidand ufenamate.

The following NSAIDs, designated by company code number (see e.g.,Pharmaprojects), may also be used:

480156S, AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC,BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182,KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ONO3144, PR823, PV102,PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281,SY6001, TA60, TAI-901 (4-benzoyl-1-indancarboxylic acid), TVX2706,U60257, UR2301, and WY41770.

Finally, NSAIDs which may also be used include the salicylates,specifically acetyl salicylic acidand the phenylbutazones, andpharmaceutically acceptable salts thereof.

In addition to indomethacin, other preferred NSAIDS are acetylsalicyclic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen,ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac andtolmetin.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain inhibitors of the biosynthesis of the leukotrienes such as aredisclosed in EP 138,481 (Apr. 24, 1985), EP 115,394 (Aug. 8, 1984), EP136,893 (Apr. 10, 1985), and EP 140,709 (May 8, 1985), which are herebyincorporated herein by reference.

The compounds of the Formula I may also be used in combination withleukotriene antagonists such as those disclosed in EP 106,565 (Apr. 25,1984) and EP 104,885 (Apr. 4, 1984) which are hereby incorporated hereinby reference and others known in the art such as those disclosed in EPApplication Nos. 56,172 Jul. 21, 1982) and 61,800 Jun. 10, 1982); and inU.K. Patent Specification No. 2,058,785 Apr. 15, 1981), which are herebyincorporated herein by reference.

Pharmaceutical compositions comprising the Formula I compounds may alsocontain as the second active ingredient, prostaglandin antagonists suchas those disclosed in EP 11,067 (May 28, 1980) or thromboxaneantagonists such as those disclosed in U.S. Pat. No. 4,237,160. They mayalso contain histidine decarboxylase inhibitors such asα-fluoromethyl-histidine, described in U.S. Pat. No. 4,325,961. Thecompounds of the Formula I may also be advantageously combined with anH₁ or H₂ -receptor antagonist, such as for instance acetamazole,aminothiadiazoles disclosed in EP 40,696 (Dec. 2, 1981), benadryl,cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine,terfenadine and like compounds, such as those disclosed in U.S. Pat.Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceuticalcompositions may also contain a K⁺ /H⁺ ATPase inhibitor such asomeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Compounds of Formula I may also be usefully combined with most cellstabilizing agents, such as1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane and relatedcompounds described in British Patent Specifications 1,144,905 and1,144,906. Another useful pharmaceutical composition comprises theFormula I compounds in combination with serotonin antagonists such asmethysergide, the serotonin antagonists described in Nature, Vol. 316,pages 126-131, 1985, and the like. Each of the references referred to inthis paragraph is hereby incorporated herein by reference.

Other advantageous pharmaceutical compositions comprise the Formula Icompounds in combination with anti-cholinergics such as ipratropiumbromide, bronchodilators such as the beta agonist salbutamol,metaproterenol, terbutaline, fenoterol and the like, and theanti-asthmatic drugs theophylline, choline theophyllinate andenprofylline, the calcium antagonists nifedipine, diltiazem,nitrendipine, verapamil, nimodipine, felodipine, etc. and thecorticosteroids, hydrocortisone, methylprednisolone, betamethasone,dexamethasone, beclomethasone, and the like.

Compounds of Formula I' can be prepared according to the followingmethods. Temperatures are in degree Celsius.

The starting methoxy phenylhydrazines II are either commerciallyavailable or are described in the chemical literature as are theacetamidophenols XXVI. The benzyl phenylhydrazine starting materials IIIare prepared as described in EP 166,591 (17102 IA) and the ketones IVand XXXI are prepared as described in EP 166,591 and EP 275,667 (17496IA). The 2-(halomethyl)quinolines VII are available from literaturemethods described in "Quinolines" Parts I and II, G. Jones (ED.), JohnWiley & Sons, Toronto, 1977 and 1982. The preparation of VII byhalogenation of the corresponding 2-methylquinolines is also describedin the Jones' volumes. The benzyl halides, (R¹⁰)2 PhCH₂ -Hal, arereadily prepared and many such compounds are described in the prior art,such as U.S. Pat. No. 4,808,608 (17323 IB). Hal in VII and (R¹⁰)₂ PhCH₂-Hal represents Cl, Br or I.

Many syntheses of indoles are well-known in the chemical literature: seefor example, "Heterocyclic compounds" Volume 25, Parts I, II, III, W. J.Houlihan (Ed.), Interscience, J. Wiley & Sons, N.Y., 1979, and "TheChemistry of Indoles" by R. J. Sundberg, Academic Press, N.Y., 1970. Oneof the most common syntheses is known as the Fischer Indole Synthesis,and is abbreviated in the following methods as "Fischer".

The --CO₂ H and --CO₂ R¹² groups in the intermediates and final productsin the various methods can be transformed to other representatives of Qsuch as --CONHS(O)₂ R¹⁴, --NHS(O)₂ R¹⁴, --CONR¹⁵ R¹⁵, --CH₂ OH ortetrazol-5-yl by the methodology described in U.S. Pat. No. 4,808,608.The preparation of the pro-drug forms (Q is --CO₂ R¹⁷) from the acidsmay be effected by the methodology of EP 104,885.

It will be apparent to one skilled in the art that the variousfunctional groups (R¹, R², Y, Q, etc.) must be chosen so as to becompatible with the chemistry being carried out. Such compatibility canoften be achieved by protecting groups, or by specific variations in thesequence of the reactions.

When R⁵ is S--R⁷, the corresponding sulfoxides and sulfones can beprepared by oxidation of the sulfides with one or two equivalents of anoxidizing agent such as m-chloroperbenzoic acid or monoperoxyphthalicacid or oxone (Trost, J. Org. Chem., 1988, pg. 532).

Many of the following methods involve a basic hydrolysis of an esterfunction to obtain the corresponding carboxylic acid. In all cases, thefree acid is obtained by acidification of the reaction mixture with asuitable acid such as hydrochloric, sulfuric, acetic, trifluoroaceticacid, etc. ##STR7##

Method 1

Intermediate V is prepared by a Fischer reaction betweenbenzylphenylhydrazine III and ketone IV, followed by hydrolysis with anaqueous solution of an alkali hydroxide or other suitable hydroxide inmixture with a suitable water miscible organic solvent such astetrahydrofuran (THF) or methanol (MeOH). The methoxy acid V isdemethylated by heating with an alkali salt of an aliphatic thiol in asuitable solvent such as hexamethylphosphorictriamide (HMPA) orN-methylpyrrolidone (NMP). The reaction mixture is acidified and thecrude acid so obtained is converted to the methyl ester VI by treatmentwith diazomethane. The phenol VI is coupled to the 2-halomethylquinolineVII, by stirring with a base (preferably an alkali hydride or carbonate)in a suitable solvent such as dimethyl formamide (DMF), NMP, acetone orthe like. The resulting ester is hydrolysed by base to yield VIII, acompound of Formula I'.

When intermediate V contains a sulfide group attached to position 3,treatment with a Lewis acid, such as AlCl₃, and an aliphatic thiol,simultaneously effects demethylation and removes the sulfide group.Suitable solvents for this reaction are methylene chloride,1,2-dichloroethane, etc. The resulting acid is then converted to themethyl ester IX with diazomethane. A Friedel-Crafts reaction between IXand an acid chloride, R⁷ COCl, simultaneously introduces the acylsubstituent into the 3-position of the indole ring and onto the phenolichydroxyl group. The acyl group is removed from the phenol by treatmentwith sodium methoxide in MeOH to yield acylphenol X. Phenol X is coupledwith VII as described for the coupling of VI and VII above. In thesecoupling reactions, it is at times advantageous to add a catalyst suchas potassium iodide or tetrabutylammonium bromide, especially when Halis chlorine. A final hydrolysis yields compound XI. ##STR8##

Method 2

Intermediate XII is prepared by a Fischer reaction between methoxyphenylhydrazine II and ketone IV. Alkylation of the indole nitrogen, afterdeprotonation using potassium hexamethyldisilazane in an ether solventsuch as tetrahydrofuran (THF), with an alkyl or aralkyl halide affordsXIII.

The methoxy group in XIII is removed using the conditions of Method 1.The corresponding phenol XIV is now coupled with the2-halomethylquinoline VII by stirring with a base (preferably an alkalihydride or carbonate) in a suitable solvent such as DMF, NMP or thelike. The resulting ester is hydrolysed using base to yield XV acompound of Formula I'.

When intermediate XIII contains a sulfide at position 3, treatment witha Lewis acid such as AlCl₃ and an aliphatic thiol simultaneously effectsdemethylation and removes the sulfide group. Suitable solvents for thisreaction are dichloromethane or dichloroethane. In a variation of Method1, the phenolic hydroxyl in XVI is first acylated with the reagent R⁷COCl (XVII) in the presence of a weak base such as triethylamine. AFriedel-Crafts reaction is then carried out on the O-acylatedintermediate, with an additional mole of XVII and AlCl₃, to yield theintermediate XVIII. Acyl ester XVIII may then be reduced to a 3-alkylindole XIV using sodium cyanoborohydride in dichloroethane using zinciodide as catalyst.

Acyl ester XVIII is cleaved to the indole phenol by hydrolysis withsodium methoxide in methanol and is coupled to 2-halomethyl quinolineVII using a base such as an alkali hydride or carbonate in a solventsuch as DMF or NMP. Hydrolysis of the resulting compound using baseyields the compound XIX. ##STR9##

Method 3

A suitably substituted aminophenol XX is protected on oxygen by the useof pivaloyl chloride dissolved in CH₂ Cl₂ using triethyl amine as base.The pivaloate ester XXI is then diazotized using hydrochloric acid andsodium nitrite in an aqueous solvent and the transient diazonium speciesreduced in situ to the hydrazine XXII using sodium hydrosulfite inwater. Benzylation of the hydrazine is effected as described in Method1.

The O-pivaloyl-N-benzylhydrazine XXIII is subjected to a Fischerindolization using the appropriate ketone IV to produce the indole XXIV.Cleavage of the O-pivaloyl group using sodium methoxide in methanoltransforms the product into the phenolic indole VI which is converted tothe products of Formula I' as described in Method 1. ##STR10##

Method 4

The pivaloyloxyphenylhydrazine XXII is used directly in the Fischerindolization using ketone IV. N-Alkylation of the indole XXV, asdescribed in Method 2, followed by removal of the pivaloyl group asdescribed, yields the phenolic indole XIV which is converted asdescribed in Method 2 to the products of Formula I' ##STR11##

Method 5

A suitable N-acetylated aminophenol XXVI is reacted with VII using analkali hydride or carbonate, such as potassium carbonate as a base in apolar solvent like DMF or NMP. The quinolinylmethoxy acetanilide XXVIIis then de-acetylated using standard basic conditions, preferably usingalcoholic potassium hydroxide under reflux to produce thequinolinylmethoxy aniline derivative XXVIII. Conversion of thequinolinylmethoxy aniline derivative to the hydrazine analogue XXIX iseffected through reduction of the intermediate diazonium salt usingsodium hydrosulfite in an aqueous medium.

The hydrazine XXIX is then N-benzylated using a benzyl halide in anorganic solvent such as methylene chloride containing an amine base suchas diisopropylethylamine and preferably tetra-n-butylammonium bromide ascatalyst.

The hydrazine XXX is then processed using a Fischer indolization withketone IV according to Methods 1, 2, 3 and 4 to produce compounds ofFormula I'. ##STR12##

Method 6

Hydrazine XXIX may also be transformed directly to unsubstituted indolesby a Fischer reaction with various ketones like XXXI. N-Alkylation ofthe indoles is effected using the conditions described in Method 2 toproduce quinolinylmethoxyindole alkanoate esters XXXII. Such esters aretransformed to ketones or carbinols via Grignard conditions using alkylmagnesium halides in ether solvents like diethyl ether or through theuse of lithium aluminum hydride in ether solvents like THF. Thecarbinols XXXIV so produced may be further transformed into estercompounds of the present invention by reacting with α-halo esters XXXVusing sodium hydride as base in a suitable solvent like THF. Subsequenthydrolysis of the esters using Method 1 leads to acid compounds ofFormula I'. ##STR13##

Method 7

Phenol XXXVII is obtained by treatment of XII (R⁵ =S--R⁷) with a Lewisacid and a thiol, as in Method 1 for the conversion of V to IX. CompoundXXXVIII is then obtained by reaction of XXXVII with VII in the presenceof a base in a suitable solvent, as described for the conversion of VIto VIII in Method 1. The introduction of R⁵ in XXXIX is convenientlyeffected by an electrophilic reaction between XXXVIII and R⁵ --Cl (R⁵not=X¹ --R⁶). Such reactions are frequently catalysed by Lewis acids orproton acids such as AlCl₃, SnCl₄, TiCl₄, BBr₃, HCl, HBr and the like.They may be carried out in a variety of solvents, with a preference fornon-protonic solvents such as dichloromethane, 1,2-dichloroethane,nitromethane, chlorobenzene and the like. It will be obvious to oneskilled in the art, that the chlorine in R⁵ --Cl, in this and the otherMethods, may often be replaced by another halogen or by a hydroxy group,or R⁵ -- Cl may be replaced by an acid anhydride (R⁷ CO)₂ O. Analternative synthesis of XXXIX is to effect a Fischer reaction betweencompounds IV and XXIX. Introduction of R⁸ into XXXIX, is accomplished byalkylation with R⁸ --Hal and a base as described previously for Methods2, 4 and 6. Finally, hydrolysis of the ester will yield XV.Alternatively, the ester group in XXXIX can be hydrolysed, and thecorresponding free acid (R¹² =H) alkylated on the indole nitrogen withR⁸ --Hal and an aqueous base, such as NaOH, and a phase-transfercatalyst, such as methyltrioctylammonium chloride. Alkylation of theacid corresponding to XXXIX (R¹² =H) can also be effected using a strongbase such as sodium hydride in a solvent such as DMF. This latterprocedure usually gives the ester of XV in which the carboxyl group hasalso been alkylated. The free acid XV can be obtained by standardhydrolysis procedures. If R⁸ in XV or the ester precursor of XV isalkenyl, it can be reduced to alkyl using hydrogen gas, and a Pt or Pdcatalyst in a suitable solvent, at atmospheric pressure. ##STR14##

Method 8

Compound XL may be prepared either by the coupling of VI to VII(Method 1) or by a Fischer reaction between IV and XXX (Method 5).Compound XL may be desulfurized by treatment with a Lewis acid such asAlCl₃, or by reduction with Raney nickel, to give compound XLI. AFriedel-Crafts reaction on XLI with the reagent R⁷ COCl and a Lewis acidcatalyst such as AlCl₃ yields the 3-acyl derivative XLII, hydrolysis ofwhich yields XI. In the Friedel-Crafts reaction, carbon monoxide may belost and compound XLIII is formed; hydrolysis under standard conditionsthen yields XLIV. The formation of XLIII occurs when the cation R⁷⁺ isespecially stable and when the reagents R⁷ COCl and the Lewis acid aremixed before adding XLI. If the Lewis acid is added last, the mainproduct is usually the acylated compound XLII. If a milder Lewis acidsuch as TiCl₄ is used, the main product is also XLII.

It will be obvious to one skilled in the art that the reagent R⁷ COClcan often be replaced by R⁷ CO-Hal (Hal=F, Br, or I) or (R⁷ CO)₂ O.##STR15##

Method 9

Indole phenol VI which may be prepared according to Methods 1 or 2 istransformed to a phenol triflate XLV by treatment with trifluoromethylsulfonic anhydride (Tf₂ O) in a solvent like pyridine indichloromethane. The phenol triflate may be carboxymethylated to acompound like XLVI under palladium acetate catalysis in an atmosphere ofcarbon monoxide, a phosphine ligand like1,1-bis(diphenylphosphinoferrocene) enhances this reaction. Reduction ofthe carboxymethylated indole may be effected with a variety of hydridereducing agents. Conveniently diisobutylaluminumhydride is used in THFon the hydrolysed ester. The reduced carbinol product XLVII isconveniently oxidized to a formylated derivative XLVIII with manganesedioxide in methylene chloride as a typical solvent. Aldehyde XLVIII canthen be homologated under carbanion conditions, typically using Wittigreagent XLIX (see U.S. Pat. 4,851,409) as shown in the method, underanhydrous conditions in an ethereal solvent like THF. The temperature ofthis reaction is typically from -70° C. to room temperature. Indolestyryl quinoline analogues (trans) L are thus formed. Furthertransformation of the styryl system may be effected by catalyticreduction using H₂ and Pd/C in an organic solvent like ethyl acetate toyield the saturated compound LI. ##STR16##

Method 10

Indole thio analogues of I' such as LIX are conveniently prepared by thesequence shown in Method 10. The treatment of compound V with BBr₃ in achlorinated solvent such as CH₂ Cl₂ cleaves both the methyl ether andthe indole N-benzyl group and cyclizes the product to an indole lactamLII. Derivatization of this compound as an N,N-dimethylthiocarbamoylindole LIII followed by thermal rearrangement at >200° C. gives rise toan N,N-dimethylcarbamoylthiondole derivative LTV. Depending on theduration of heating, dethiolation (R⁵ =--S--t--Bu→R⁵ =H) may also takeplace. The hydrolysis of LIV may be effected using strong base,typically sodium methoxide in methanol is used. Spontaneous formation ofdisulfide LV may occur in this reaction. The reduction of LV can beachieved using triphenylphosphine in aqueous dioxane to produce LVI.Coupling of LVI to an appropriately substituted quinoline derivative VIItakes place under organic base catalysis; typically triethylamine, in anorganic solvent such as methylene chloride, is used. Transformation ofindole LVII to an N-benzylated derivative LIX is achieved under standardconditions described in Method 2 or by benzylation with an appropriatebenzyl halide using a base such as sodium hydride in a non-proticsolvent such as dimethylformamide. ##STR17##

Method 11

The preparation of the various definitions of Q is outline in Method 11,starting from the readily available carboxylic acid derivative --CO₂R¹². It will be obvious to one skilled in the art that many of thereactions indicated are reversible. Thus, by way of illustration, the--CN group can serve as the starting material to prepare the amide andcarboxylic acid functional groups. The reactions depicted in Method 11as well as methods for synthesis of the sulfonamide group (--S(O)₂NHR¹⁵) are well-known in the art. See, for instance the following textbooks:

1. J. March, Advanced Organic Chemistry, 3rd ed., J. Wiley and Sons,Toronto, 1985.

2. S. R. Sandler and W. Karo, Organic Functional Group Preparations, I &II, Academic Press, Toronto, 1983 and 1986. ##STR18##

Method 12

3-Unsubstituted indole analog XLI, described in Method 8, may be moreconveniently prepared by the process illustrated in Method 12 anddescribed in greater detail in copending application Ser. No. 642,778,filed Jan. 16, 1991 and in D. Zhao, et al., J. Org. Chem., 56, 3001,(1991). Thus, the suitably substituted hydrazine XXX is reacted with thesuitably substituted methyl ketone LX to provide the hydrazone LXI. Thehydrazone LXI is treated with a combination of phosphorous pentoxide andmethane sulfonic acid, optionally in the presence of a suitableco-solvent, such as sulfolane, dichloromethane and the like, to providethe 3-unsubstituted indole XLI.

Representative Compounds

Table I illustrates the compounds of the present invention.

                  TABLE I                                                         ______________________________________                                         ##STR19##                                                                           Ex. No.        R.sup.1                                                 ______________________________________                                               1              H                                                              2A             F                                                              2B             OMe                                                     ______________________________________                                    

Assays for Determining Biological Activity

Compounds of Formula I can be tested using the following assays todetermine their mammalian leukotriene biosynthesis inhibiting activity.

Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay

Rats under ether anesthesia are injected (i.p.) with 8 mL of asuspension of sodium caseinate (6 grams in ca. 50 mL water). After 15-24hr. the rats are sacrificed (CO₂) and the cells from the peritonealcavity are recovered by lavage with 20 mL of buffer (Eagles MEMcontaining 30 mM HEPES adjusted to pH 7.4 with NaOH). The cells arepelleted (350× g, 5 min.), resuspended in buffer with vigorous shaking,filtered through lens paper, recentrifuged and finally suspended inbuffer at a concentration of 10 cells/mL. A 500 mL aliquot of PMNsuspension and test compound are preincubated for 2 minutes at 37° C.,followed by the addition of 10 mM A-23187. The suspension is stirred foran additional 4 minutes then bioassayed for LTB₄ content by adding analiquot to a second 500 mL portion of the PMN at 37° C. The LTB₄produced in the first incubation causes aggregation of the second PMN,which is measured as a change in light transmission. The size of theassay aliquot is chosen to give a submaximal transmission change(usually -70%) for the untreated control. The percentage inhibition ofLTB₄ formation is calcuated form the ratio of transmission change in thesample to the transmission change in the compound-free control.

Human Polymorphonuclear (PMN) Leukocyte LTB₄ Assay

A. Preparation of Human PMN. Human blood was obtained by antecubitalvenepuncture from consenting volunteers who had not taken medicationwithin the previous 7 days. The blood was immediately added to 10% (v/v)trisodium citrate (0.13M) or 5% (v/v) sodium heparin (1000 IU/mL). PMNswere isolated from anticoagulated blood by dextran sedimentation oferythrocytes followed by centrifugation through Ficoll-Hypaque (specificgravity 1.077), as described by Boyum (Scand. J. Clin. Lab. Invest., 21(Supp. 97), 77(1968)). Contaminating erythrocytes were removed by lysisfollowing exposure to ammonium chloride (0.16M) in Tris buffer (pH7.65), and the PMNs resuspended at 5×10⁵ cells/mL in HEPES (15mM)-buffered Hanks balanced salt solution containing Ca²⁺ (1.4 mM) andMg²⁺ (0.7 mM), pH 7.4. Viability was assessed by Trypan blue exclusionand was typically greater than 98%.

B. Generation and Radioimmunoassay of LTB₄. PMNs (0.5 mL; 2.5×10⁵ cells)were placed in plastic tubes and incubated (37° C., 2 min) with testcompounds at the desired concentration or vehicle (DMSO, finalconcentration 0.2%) as control. The synthesis of LTB₄ was initiated bythe addition of calcium ionophore A23187 (final concentration 10 mM) orvehicle in control samples and allowed to proceed for 5 minutes at 37°C. The reactions were then terminated by the addition of cold methanol(0.25 mL) and samples of the entire PMN reaction mixture were removedfor radioimmunoassay of LTB₄.

Samples (50 mL) of authentic LTB₄ of known concentration inradioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodiumEDTA 0.1 mM; Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN reactionmixture diluted 1:1 with RIA buffer were added to reaction tubes.Thereafter [³ H]-LTB₄ (10 nCi in 100 mL RIA buffer) and LTB₄ -antiserum(100 mL of a 1:3000 dilution in RIA buffer) were added and the tubesvortexed. Reactants were allowed to equilibrate by incubation overnightat 4° C. To separate antibody-bound from free LTB₄, aliquots (50 mL) ofactivated charcoal (3% activated charcoal in RIA buffer containing 0.25%Dextran T-70) were added, the tubes vortexed, and allowed to stand atroom temperature for 10 minutes prior to centrifugation (1500×g; 10 min;4° C.). The supernatants containing antibody-bound LTB₄ were decantedinto vials and Aquasol 2 (4 mL) was added. Radioactivity was quantifiedby liquid scintillation spectrometry. Preliminary studies establishedthat the amount of methanol carried into the radioimmunoassay did notinfluence the results. The specificity of the antiserum and thesensitivity of the procedure have been described by Rokach et al.(Prostaglandins Leukotrienes and Medicine 1984, 13, 21.) The amount ofLTB₄ produced in test and control (approx. 20 ng/10⁶ cells) samples werecalculated. Inhibitory dose-response curves were constructed using afour-parameter algorithm and from these the IC₅₀ values were determined.

Asthmatic Rat Assay

Rats are obtained from an inbred line of asthmatic rats. Both female(190-250 g) and male (260-400 g) rats are used.

Egg albumin (EA), grade V, crystallized and lyophilized, is obtainedfrom Sigma Chemical Co., St. Louis. Aluminum hydroxide is obtained fromthe Regis Chemical Company, Chicago. Methysergide bimaleate was suppliedby Sandoz Ltd., Basel.

The challenge and subsequent respiratory recordings are carried out in aclear plastic box with internal dimensions 10×6×4 inches. The top of thebox is removable; in use, it is held firmly in place by four clamps andan airtight seal is maintained by a soft rubber gasket. Through thecenter of each end of the chamber a Devilbiss nebulizer (No. 40) isinserted via an airtight seal and each end of the box also has anoutlet. A Fleisch No. 0000 pneumotachograph is inserted into one end ofthe box and coupled to a Grass volumetric pressure transducer (PT5-A)which is then connected to a Beckman Type R Dynograph throughappropriate couplers. While aerosolizing the antigen, the outlets areopen and the pneumotachograph is isolated from the chamber. The outletsare closed and the pneumotachograph and the chamber are connected duringthe recording of the respiratory patterns. For challenge, 2 mL of a 3%solution of antigen in saline is placed into each nebulizer and theaerosol is generated with air from a small Potter diaphragm pumpoperating at 10 psi and a flow of 8 liters/minute.

Rats are sensitized by injecting (subcutaneously) 1 mL of a suspensioncontaining 1 mg EA and 200 mg aluminum hydroxide in saline. They areused between days 12 and 24 postsensitization. In order to eliminate theserotonin component of the response, rats are pretreated intravenously 5minutes prior to aerosol challenge with 3.0 mgm/kg of methysergide. Ratsare then exposed to an aerosol of 3% EA in saline for exactly 1 minute,then their respiratory profiles are recorded for a further 30 minutes.The duration of continuous dyspnea is measured from the respiratoryrecordings.

Compounds are generally administered either orally 1-4 hours prior tochallenge or intravenously 2 minutes prior to challenge. They are eitherdissolved in saline or 1% methocel or suspended in 1% methocel. Thevolume injected is 1 mL/kg (intravenously) or 10 mL/kg (orally). Priorto oral treatment rats are starved overnight. Their activity isdetermined in terms of their ability to decrease the duration ofsymptoms of dyspnea in comparison with a group of vehicle-treatedcontrols. Usually, a compound is evaluated at a series of doses and anED₅₀ is determined. This is defined as the dose (mg/kg) which wouldinhibit the duration of symptoms by 50%.

The invention is further defined by reference to the following examples,which are intended to be illustrative and not limiting. All temperaturesare in degrees Celsius. ##STR20##

EXAMPLE 13-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6-fluoroquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid, sodium salt

Step A: 2-Bromomethyl-6-fluoroquinoline

To a solution of 6-fluoro-2-methylquinoline (see C. M. Leir, J. Org.Chem., vol 42, pp 911-913, 1977) (21.67 g) in carbon tetrachloride (700mL) were added N-bromosuccinimide (26.32 g) and benzoyl peroxide (1.62g). The mixture was brought to reflux with two spot lights of 150 Watts.The mixture was irradiated for 24 hours at reflux. The mixture was thencooled to room temperature, evaporated to dryness and chromatographed onflash silica gel using pure toluene as eluant to give, as the slowerrunning compound, a beige solid (11.9 g); m.p. 90°-92° C.

Step B: Methyl3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6-fluoroquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate

To a solution of Methyl3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate(See EP419,049, Example 1, Step C) (322 mg) in acetonitrile (7 mL) wereadded solid cesium carbonate (456 mg) and2-bromomethyl-6-fluoroquinoline (190 mg) from Step A. The mixture wasstirred at room temperature for 18 hr. The mixture was poured into 25%aqueous NH₄ OAc (50 mL), extracted with ethyl acetate (2×50 mL), washedwith brine (50 mL), dried (MgSO₄) and evaporated to dryness. The residuewas chromatographed on flash silica gel using ethyl acetate:toluene(5:95) as eluant to give the title compound as a white solid; m.p.165°-167° C.

Step C:

3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6-fluoroquinolin-2-ylmethoxy)indol-2-yl]2,2-dimethylpropanoicacid, sodium salt

The compound (302 mg) from Step B was hydrolyzed by dissolving it in THF(4 mL), MeOH (2 mL) and 2N LiOH (1 mL). The solution was heated at 70°C. for 6 hr. The solution was cooled to room temperature, diluted withH₂ O (50 mL), acidified with glacial AcOH to pH5 and then diluted with25% NH₄ OAc (50 mL). The mixture was extracted with ethyl acetate (3×50mL), washed with brine (50 mL) and dried (MgSO₄). The solution wasevaporated to dryness, coevaporated with toluene (50 mL) to provide thetitle acid as a white solid, m.p. 213°-215° C. The title compound wasprepared as follows: the acid was suspended in ethanol (3 mL) andtreated with 1.0N NaOH (1 equiv.) diluted with H₂ O (5 mL) andlyophilized to give the title product.

Anal. Calc'd for C₃₄ H₃₃ N₂ O₃ SClFNa.H₂ O; Calcd: C, 63.29: H, 5.47; N,4.34; Found: C, 63.42; H, 5.38; N, 4.07.

EXAMPLE 2A3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6,7-difluoroquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid, sodium salt EXAMPLE 2B3-[N-(p-chlorobenzyl-3(t-butylthio)-5-(6-fluoro-7-methoxyquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid, sodium salt

Step A: 6,7-Difluoro-2-methylquinoline

Crotonaldehyde (226.34 g, 3.23 mol) in 100 mL of 2-butanol was addeddropwise to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23mol), p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 Lof 2-butanol. After 2 hours of heating 2.7 L of solvent was removedunder vacuum at ca. 60° C. Then 2 L of toluene was added to the reactionmixture followed by removal of 2.5-3 L of solvent or until a very pastysolid formed. THF (2 L) was added and the mixture heated 30 min. afterwhich it was cooled to 0° C. The solid was collected and washed with THFuntil pure by tlc. The solid was then dissolved in aq. K₂ CO₃ /EtOAc andthe organic phase separated. The aqueous phase was extracted with EtOAc(2×) and the organic phases combined, dried over MgSO₄ and the solventremoved. The product was crystallized in the minimum amount of EtOAc togive 328.08 g (57%) of the title compound.

¹ H NMR (CD₃ COCD₃): δ 8.19 (1H, d), 7.75 (2H, m), 7.4 (1H, d), 2.64(3H, s).

Step B: 2-bromomethyl-6,7-difluoroquinoline

Following the procedure of Example 1, Step A, but starting with6,7-difluoro-2-methylquinoline from Step A, the title compound wasobtained as a white solid; m.p. 113°-115° C.

Step C: Methyl3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6,7-difluoroquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate

Following the procedure of Example 1, Step B but using2-bromomethyl-6,7-difluoroquinoline from Step B, the title compound wasobtained as a white solid; m.p. 171°-173° C.

Step D:

3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6,7-difluoroquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid, sodium salt and

3-[N-(p-chlorobenzyl-3(t-butylthio)-5-(6-fluoro-7-methoxyquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoicacid, sodium salt

The compound (423 mg) from Step C was hydrolyzed by dissolving it in THF(6 mL), MeOH (6 ml) and 2N LiOH (1.3 mL). The solution was heated at 70°C. for 6 hr. The solution was diluted with H₂ O (50 mL), acidified withglacial AcOH to pH5, diluted with 25% NH₄ OAc (50 mL) extracted withethyl acetate (3× 50 mL), washed with brine (50 mL), and dried (MgSO₄).The solution was evaporated to dryness, co-evaporated with toluene (50mL) to give a mixture of both title acids. The mixture was dissolved ina (1:1) mixture of CH₂ Cl₂ : THF and chromatographed on flash silica gelusing a mixture of ethyl acetate:hexane:acetic acid (30:70:2.5) aseluant to afford the 6,7-difluoro acid in the fast fraction (whitesolid; m.p. 218°-220° C.), and the 6-fluoro-7-methoxy acid in the slowfraction (white solid; m.p. 230° C. (d) in a (3:1) ratio.

Both sodium salts were prepared as described in Example 1, Step C togive the title products.

6,7-difluoro derivative: (Example 2A)

Anal. Calcd. for C₃₄ H₃₂ N₂ O₃ SClF₂ Na. 3H₂ O; Calcd: C, 58.40; H,5.48; N, 4.01; Found: C, 58.12; H, 5.21; N, 4.14.

6-fluoro-7-methoxy derivative: (Example 2B)

Anal. Calcd. for C₃₅ H₃₅ N₂ O₄ SClFNa.2H₂ O; Calcd: C, 60.64; H, 5.67;N, 4.04; Found: C, 60.93; H, 5.22; N, 4.12.

What is claimed is:
 1. A compound of the Formula I: ##STR21## wherein:R¹ is H, F or MeO;or a pharmaceutically acceptable salt thereof.
 2. Acompound of claim 1, wherein R¹ is H.
 3. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 1and a pharmaceutically acceptable carrier.
 4. A method of preventing thesynthesis, the action, or the release of SRS-A or leukotrienes in amammal which comprises administering to said mammal an effective amountof a compound of claim
 1. 5. A method of treating asthma in a mammalcomprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of claim
 1. 6. A methodof treating inflammatory diseases of the eye in a mammal which comprisesadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1.